Neoadjuvant Darolutamide Alone or in Combination With Standard Therapy for Stage II-IIIA, AR+, TNBC

Inclusion criteria

• Signed and dated written informed consent as well as the ability to understand and the willingness to sign written consent prior to study registration
• Male or female ≥ 18 years of age on the day of signing informed consent
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Histologically confirmed newly diagnosed breast cancer with the following requirements:
• \<10% staining for estrogen receptor (ER) and progesterone receptor (PR) by immunohistochemistry (IHC)
• HER2 negative by fluorescence in situ hybridization (FISH)
• AR positive: defined as ≥ 80% staining for AR by IHC
• Primary tumor clinically or radiographically ≥ 1cm in size or stage II-IIIA and eligible for neoadjuvant treatment
• Absolute neutrophil count (ANC) ≥ 1500/µL (≤ 28 days prior to first dose of protocol-indicated treatment)
• Platelets ≥ 100,000/µL (≤ 28 days prior to first dose of protocol-indicated treatment)
• Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/L (≤ 28 days prior to first dose of protocol-indicated treatment)
• Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min (as calculated by the Cockcroft-Gault Formula or calculated/measured by an alternative established institutional standard consistently applied across participants at the site) (≤ 28 days prior to first dose of protocol-indicated treatment)
• Total bilirubin ≤ 1.5 times institutional upper limit of normal (ULN), or direct bilirubin ≤ ULN for participants with total bilirubin \> 1.5 x ULN (≤ 28 days prior to first dose of protocol-indicated treatment)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) ≤ 2.5 times institutional upper limit of normal (ULN) (≤ 28 days prior to first dose of protocol-indicated treatment)
• Calcium ≤ 11.5 mg/dL or ≤ 2.9 mmol/L; in patients with albumin outside the normal range, calcium (corrected for albumin) must be ≤ 11.5 mg/dL or ≤ 2.9 mmol/L (≤ 28 days prior to first dose of protocol-indicated treatment)
• Women must not be breastfeeding and further agree to not breastfeed during study treatment and for at least 120 days after completion of treatment
• A woman of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test during screening within 21 days prior to receiving first dose of protocol-indicated treatment, and must agree to follow instructions for using acceptable contraception from the time of signing consent, and until at least 120 days after completion of treatment
• Men must refrain from donating sperm for at least 120 days after completion of treatment
• A man able to father children who is sexually active with a WOCBP must agree to follow instructions for using acceptable contraception, from the time of signing consent, and until at least 120 days after completion of treatment

Exclusion criteria

• Non-resectable breast cancer as assessed by the primary treating surgeon or evidence of metastatic disease
• Malignancies other than TNBC within 5 years prior to randomization, with the exception of those with a negligible risk of metastases or death and treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix or basal or squamous cell skin cancer)
• Patient is pregnant or breastfeeding
• Patients with moderate hepatic impairment (Child-Pugh Class B cirrhosis or higher)
• Is currently participating in or within four weeks prior to receiving first dose of study treatment in a study of an investigational agent or investigational device
• Participants who have entered the follow-up phase of an investigational study may participate as long as it has been four weeks after the last dose or last exposure to the previous investigational agent or investigational device
• Recipient of previous allogeneic tissue/solid organ transplant
• Known severe hypersensitivity (≥ Grade 3) to study drug, pembrolizumab, carboplatin, doxorubicin/epirubicin, paclitaxel, or cyclophosphamide and/or any of the excipients of these drugs
• History of myocarditis or pericarditis or other known underlying heart disease that is clinically significant by investigator judgment (for example, cardiomyopathy, congestive heart failure with New York Heart Association \[NYHA\] functional classification III or IV, symptomatic arrhythmia not controlled by medication, unstable angina, history of acute myocardial infarction). History of cerebrovascular accident (including transient ischemic attack \[TIA\]) within the past six months (24 weeks) prior to starting study treatment
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection/sepsis, or psychiatric illness/social situations that would limit compliance with study requirements
• Known conditions that would preclude the use of checkpoint inhibitors